In vitro assessment of farnesoid X receptor antagonism to predict drug-induced liver injury risk
Drug-induced liver injury (DILI) continues to be a major cause of drug attrition and restrictive labeling. Given the importance of farnesoid X receptor (FXR) in bile acid homeostasis, drug-related FXR antagonism may be an important mechanism of DILI. However, a comprehensive assessment of this phenomenon broadly in the context of DILI is lacking. As such, we used an orthogonal approach comprising a FXR target gene assay in primary human hepatocytes and a commercially available FXR reporter assay to investigate the potential FXR antagonistic effects of an extensive test set of 159 compounds with and without association with clinical DILI. Data were omitted from analysis based on the presence of cytotoxicity to minimize false positive assay signals and other complications in data interpretation. Based on the experimental approaches employed and corresponding data, the prevalence of FXR antagonism was relatively low across this broad DILI test set, with 16-24% prevalence based on individual assay results or combined signals in both assays. Moreover, FXR antagonism was not highly predictive for identifying clinically relevant hepatotoxicants retrospectively, where FXR antagonist classification alone had minimal to moderate predictive value as represented by positive and negative likelihood ratios of 2.24-3.84 and 0.72-0.85, respectively. The predictivity did not increase significantly when considering only compounds with high clinical exposure (maximal or efficacious plasma exposures > 1.0 μM). In contrast, modest gains in predictive value of FXR antagonism were observed considering compounds that also inhibit bile salt export pump. In addition, we have identified novel FXR antagonistic effects of well-studied hepatotoxic drugs, including bosentan, tolcapone and ritonavir. In conclusion, this work represents a comprehensive evaluation of FXR antagonism in the context of DILI, including its overall predictivity and challenges associated with detecting this phenomenon in vitro.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:94 |
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| Enthalten in: |
Archives of toxicology - 94(2020), 9 vom: 25. Sept., Seite 3185-3200 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Norona, Leah M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.06.2021 Date Revised 16.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00204-020-02804-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM311614698 |
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| 100 | 1 | |a Norona, Leah M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a In vitro assessment of farnesoid X receptor antagonism to predict drug-induced liver injury risk |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Revised 16.06.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Drug-induced liver injury (DILI) continues to be a major cause of drug attrition and restrictive labeling. Given the importance of farnesoid X receptor (FXR) in bile acid homeostasis, drug-related FXR antagonism may be an important mechanism of DILI. However, a comprehensive assessment of this phenomenon broadly in the context of DILI is lacking. As such, we used an orthogonal approach comprising a FXR target gene assay in primary human hepatocytes and a commercially available FXR reporter assay to investigate the potential FXR antagonistic effects of an extensive test set of 159 compounds with and without association with clinical DILI. Data were omitted from analysis based on the presence of cytotoxicity to minimize false positive assay signals and other complications in data interpretation. Based on the experimental approaches employed and corresponding data, the prevalence of FXR antagonism was relatively low across this broad DILI test set, with 16-24% prevalence based on individual assay results or combined signals in both assays. Moreover, FXR antagonism was not highly predictive for identifying clinically relevant hepatotoxicants retrospectively, where FXR antagonist classification alone had minimal to moderate predictive value as represented by positive and negative likelihood ratios of 2.24-3.84 and 0.72-0.85, respectively. The predictivity did not increase significantly when considering only compounds with high clinical exposure (maximal or efficacious plasma exposures > 1.0 μM). In contrast, modest gains in predictive value of FXR antagonism were observed considering compounds that also inhibit bile salt export pump. In addition, we have identified novel FXR antagonistic effects of well-studied hepatotoxic drugs, including bosentan, tolcapone and ritonavir. In conclusion, this work represents a comprehensive evaluation of FXR antagonism in the context of DILI, including its overall predictivity and challenges associated with detecting this phenomenon in vitro | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a BSEP | |
| 650 | 4 | |a Cholestasis | |
| 650 | 4 | |a DILI | |
| 650 | 4 | |a FXR antagonism | |
| 650 | 4 | |a Hepatotoxicity | |
| 650 | 7 | |a ABCB11 protein, human |2 NLM | |
| 650 | 7 | |a ATP Binding Cassette Transporter, Subfamily B, Member 11 |2 NLM | |
| 650 | 7 | |a Bile Acids and Salts |2 NLM | |
| 650 | 7 | |a Receptors, Cytoplasmic and Nuclear |2 NLM | |
| 650 | 7 | |a farnesoid X-activated receptor |2 NLM | |
| 650 | 7 | |a 0C5V0MRU6P |2 NLM | |
| 700 | 1 | |a Fullerton, Aaron |e verfasserin |4 aut | |
| 700 | 1 | |a Lawson, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Leung, Leslie |e verfasserin |4 aut | |
| 700 | 1 | |a Brumm, Jochen |e verfasserin |4 aut | |
| 700 | 1 | |a Kiyota, Tomomi |e verfasserin |4 aut | |
| 700 | 1 | |a Maher, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Khojasteh, Cyrus |e verfasserin |4 aut | |
| 700 | 1 | |a Proctor, William R |e verfasserin |4 aut | |
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